Thank you for visiting nature.com. You are using a browser version with
limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off
compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site
without styles and JavaScript.

Subjects

Abstract

The equivalence of human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) remains controversial. Here we use genetically matched hESC and hiPSC lines to assess the contribution of cellular origin (hESC vs. hiPSC), the Sendai virus (SeV) reprogramming method and genetic background to transcriptional and DNA methylation patterns while controlling for cell line clonality and sex. We find that transcriptional and epigenetic variation originating from genetic background dominates over variation due to cellular origin or SeV infection. Moreover, the 49 differentially expressed genes we detect between genetically matched hESCs and hiPSCs neither predict functional outcome nor distinguish an independently derived, larger set of unmatched hESC and hiPSC lines. We conclude that hESCs and hiPSCs are molecularly and functionally equivalent and cannot be distinguished by a consistent gene expression signature. Our data further imply that genetic background variation is a major confounding factor for transcriptional and epigenetic comparisons of pluripotent cell lines, explaining some of the previously observed differences between genetically unmatched hESCs and hiPSCs.

Acknowledgements

We thank members of the Hochedlinger and Park laboratories for productive discussions and a critical reading of the manuscript. We also thank M. Stadtfeld for his helpful discussions and D. Melton for his generous donation of HUES2 and HUES3 lines. We are grateful to K. Folz-Donahue, M. Weglarz and L. Prickett at the Massachusetts General Hospital (MGH)/Harvard Stem Cell Institute (HSCI) flow cytometry core for their constant assistance and support. We are also thankful to the members of the Tufts Genomics Core for performing RNA-seq. Work in the Lee laboratory was supported by grants from the Robertson Investigator Award of the New York Stem Cell Foundation and from the Maryland Stem Cell Research Fund (TEDCO). A.M. and J.L.R. are supported by US National Institutes of Health (NIH) grant P01GM099117. A.M. is a New York Stem Cell Foundation Robertson Investigator. Parts of this work were supported by the Howard Hughes Medical Institute (HHMI), MGH startup funds, the Gerald and Darlene Jordan Endowed Chair for Regenerative Medicine (to K.H.) and a pilot grant from the NIH (P01GM099117 to K.H.). J.C. was supported by the Vranos Family Graduate Research Fellowship in Developmental & Regenerative Biology.